Low-dose continuous 5-fluorouracil infusion stimulates VEGF-A-mediated angiogenesis.
BACKGROUND
Tumor growth is angiogenesis-dependent. Animal studies have demonstrated that frequent administration of chemotherapeutics may have marked antiangiogenic effects and improved antitumor effects, with less severe toxic side-effects than intermittent maximum tolerated dose chemotherapy. Currently, research focused on low-dose antiangiogenic chemotherapy is increasing. We have recently reported that certain chemotherapeutics, including 5-fluorouracil (5-FU), may in fact stimulate angiogenesis in the tumor-free rat mesenteric window assay. The aim of the present study was to extend the investigation of the angiogenesis-modulating effects of 5-FU by prolonging the continuous infusion treatment time.


METHODS
Angiogenesis was induced in the mesenteric test tissue in adult male Sprague-Dawley rats by i.p. injection of VEGF-A, which is a key angiogenic factor in most tumors. During the subsequent angiogenesis, 5-FU was delivered continuously for 14 days by an osmotic pump implanted subcutaneously. The angiogenic response was analyzed by morphometry in the mesenteric windows.


RESULTS
The 14-days continuous infusion of 5-FU significantly stimulated angiogenesis. Thus the possibility that the previously reported surprising proangiogenic effect of 5-FU reflected an insufficiently long treatment period can be ruled out.


CONCLUSIONS
The finding that continuously infused 5-FU is able to stimulate angiogenesis in the present rat model of angiogenesis warrants investigation of the mechanisms behind this unexpected finding. It may further have implications for the choice of antiangiogenic chemotherapeutic schedule used for cancer patients.
Albertsson
Per
P
Department of Oncology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
Lennernäs
Bo
B
Norrby
Klas
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005472:Fluorouracil / Q000008:administration & dosage*; D055104:Infusions, Subcutaneous; D008297:Male; D008643:Mesentery / Q000098:blood supply* / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D005472:Fluorouracil